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Lipid peroxidation and iron accumulation are closely associated with neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, or neurodegeneration with brain iron accumulation disorders. Mitochondrial dysfunction, lipofuscin accumulation, autophagy disruption, and ferroptosis have been implicated as the critical pathomechanisms of lipid peroxidation and iron accumulation in these disorders. Currently, the connection between lipid peroxidation and iron accumulation and the initial cause or consequence in neurodegeneration processes is unclear. In this review, we have compiled the known mechanisms by which lipid peroxidation triggers iron accumulation and lipofuscin formation, and the effect of iron overload on lipid peroxidation and cellular function. The vicious cycle established between both pathological alterations may lead to the development of neurodegeneration. Therefore, the investigation of these mechanisms is essential for exploring therapeutic strategies to restrict neurodegeneration. In addition, we discuss the interplay between lipid peroxidation and iron accumulation in neurodegeneration, particularly in PLA2G6-associated neurodegeneration, a rare neurodegenerative disease with autosomal recessive inheritance, which belongs to the group of neurodegeneration with brain iron accumulation disorders.

Neurodegenerative diseases are characterized by the progressive loss of neurons, synapses, dendrites, and myelin in the central and/or peripheral nervous system. Actual therapeutic options for patients are scarce and merely palliative. Although they affect millions of patients worldwide, the molecular mechanisms underlying these conditions remain unclear. Mitochondrial dysfunction is generally found in neurodegenerative diseases and is believed to be involved in the pathomechanisms of these disorders. Therefore, therapies aiming to improve mitochondrial function are promising approaches for neurodegeneration. Although mitochondrial-targeted treatments are limited, new research findings have unraveled the therapeutic potential of several groups of antibiotics. These drugs possess pleiotropic effects beyond their anti-microbial activity, such as anti-inflammatory or mitochondrial enhancer function. In this review, we will discuss the controversial use of antibiotics as potential therapies in neurodegenerative diseases.